Aims
Aggressive meningioma remains incurable with neither chemo‐ nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving ...the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression.
Methods
Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression‐free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked‐down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM‐Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)‐pretreated or control IOMM‐Lee cells were implanted subcutaneously in nude mice.
Results
FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of β‐catenin, cyclin D1, p21, interleukin‐8, vascular endothelial growth factor‐A, PLAU, and epithelial‐to‐mesenchymal transition‐related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model.
Conclusions
Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.
Background: This study was to devise a prognostic model for metastatic gastric cancer patients undergoing first-line chemotherapy. Patients and methods: A retrospective analysis was carried out on ...1455 gastric cancer patients, who received first-line chemotherapy from September 1994 to February 2005. Results: At multivariate level, poor prognostic factors were no previous gastrectomy P = 0.003; relative risk (RR), 1.191; 95% confidence interval (CI) 1.061–1.338, albumin <3.6 g/dl (P = <0.001; RR, 1.245; 95% CI 1.106–1.402), alkaline phosphatase >85 U/l (P = <0.001; RR, 1.224; 95% CI 1.092–1.371), Eastern Cooperative Oncology Group performance status of two or more (P = <0.001; RR, 1.690; 95% CI 1.458–1.959), the presence of bone metastases (P = 0.001; RR, 1.460; 95% CI 1.616–1.836), and the presence of ascites (P = <0.001; RR, 1.452; 95% CI 1.295–1.628). Of 1434 patients, 489 patients (34.1%) were categorized as low-risk group (zero to one factors), 889 patients (62.0%) as intermediate-risk group (two to four factors), and 56 patients (3.9%) as high-risk group (five to six factors). Median survival durations for low, intermediate, and high-risk groups were 12.5 months, 7.0 months, and 2.7 months, respectively. Conclusions: This model should facilitate the individual patient risk stratification and thus, more appropriate therapies for each metastatic gastric cancer patient.
The hot compressive deformation mechanism and processing maps of the equiatomic FCC CoCrFeMnNi high-entropy alloy (HEA) were studied in the temperature range between 1023 and 1323 K and in the strain ...rate range between 10−3 and 10 s−1. At high strain rates above 1 s-1, strain hardening was dominant even at the very high temperature of 0.84Tm, which may be attributed to the sluggish diffusion coefficient and low stacking fault energy of the CoCrFeMnNi HEA, leading to suppression of dynamic recovery. According to the processing maps, the best condition for hot working was near 10−3 s−1 at 1323 K. Power-law breakdown and unstable flow occurred at low temperatures and high strain rates where the strain hardening was pronounced. The activation energy for plastic flow measured in the power-law creep regime when considering the dependence of elastic modulus on temperature was 312.2 kJ/mol; this value is close to the activation energy for the weighted diffusion coefficient calculated by weighting the contribution of each element in the CoCrFeMnNi HEA (284 kJ/mol). The size and fraction of the dynamically recrystallized grains increased as the strain rate decreased and the temperature increased, as in conventional metals. Both discontinuous dynamic recrystallization and continuous dynamic recrystallization (CDRX) occurred. CDRX became more distinct as the temperature increased. The deformation mechanism and behavior of the CoCrFeMnNi HEA were very similar to those of FCC pure metals in terms of the stress exponent and the effect of the stacking fault energy and diffusivity on the creep rates.
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